There is a consistent need for ready blood products for an ever-increasing surgical and trauma load, and to supplement blood bank shortages. Oxygen carrying solutions, such as hemoglobin-derived solutions can be used in place of whole blood or red blood cells for patients having a need for augmented oxygen carrying capacity. Because they are not dependent upon donor availability, such solutions can be made readily available in an emergency situation or during a blood bank shortage. Also, due to risk of infection of blood borne pathogens as a result of a blood transfusion, a patient may prefer a hemoglobin-derived solution for transfusion in place of whole blood or red blood cells. In particular, such solutions may include, but are not limited to, oxygen carriers, blood substitutes, and hemoglobin-derived compositions such as those disclosed in U.S. Pat. Nos. 6,498,141, 6,133,425, 5,464,814, 5,438,041, 5,217,648, 5,194,590, 5,061,688, and 4,826,811, the teachings of which are incorporated herein by reference in their entirety.
Stroma-free hemoglobin is known in the art to have oxygen transport and reversible oxygen (or ligand) binding capacities. However, hemoglobin solutions, while capable of carrying sufficient quantities of oxygen to support life, have presented challenges because of several undesirable side effects such as a decrease in kidney performance. These effects were thought to be due to the presence of unwanted contaminants such as bacterial endotoxin or fragments of red cell membranes (stroma) that is not removed from solution. While contaminants such as these can indeed produce renal alterations, hemoglobin solutions essentially free of such contaminants still produce substantial renal dysfunction. The cause for the renal dysfunction can be ascribed to, among other things, physiologically unacceptable amounts of unpolymerized hemoglobin tetramer.
Essentially tetramer free hemoglobin solutions can be used to replenish essentially all of a human patient's blood volume without causing vasoconstriction, renal toxicity, hemoglobinuria or other problems associated with intravenous administration of synthetic or semisynthetic oxygen carriers and blood substitutes. While these solutions provide superior efficacy, the shelf life of the product is limited since the hemoglobin polymer is known to slowly degrade to tetrameric units over time. Accordingly, what is needed is a method for maintaining the solution as a substantially tetramer free solution for an extended period to increase the shelf life of the solution.